@article {Torralvajpet.119.258566,
author = {Torralva, Phillip Randy and Janowsky, Aaron},
title = {Noradrenergic Mechanisms in Fentanyl-Mediated Rapid Death Explain Failure of Naloxone in the Opioid Crisis},
elocation-id = {jpet.119.258566},
year = {2019},
doi = {10.1124/jpet.119.258566},
publisher = {American Society for Pharmacology and Experimental Therapeutics},
abstract = {In December 2018, the Centers for Disease Control (CDC) declared fentanyl the deadliest drug in America. Opioid overdose is the single greatest cause of death in the U.S. adult population (ages 18-50), and fentanyl and its analogues (F/FA) are currently involved in \>50\% of these deaths. Anesthesiologists in the U.S. were introduced to fentanyl in the early 1970{\textquoteright}s when it revolutionized surgical anesthesia by combining profound analgesia with hemodynamic stability. However, they quickly had to master its unique side effect. F/FA can produce profound rigidity in the diaphragm, chest wall and upper airway within an extremely narrow dosing range. This effect, known as fentanyl-induced muscle rigidity or "wooden chest syndrome," is not commonly known outside of anesthesiology and is rarely known by other clinicians and researchers in addiction research/medicine. The effect is almost routinely fatal without expert airway management. This review provides relevant clinical human pharmacology and animal data demonstrating that the significant increase in the number of F/FA-induced deaths involves alpha-1 and other noradrenergic receptor-mediated mechanical failure of the respiratory and cardiovascular systems with rapid development of rigidity and airway closure. Morphine and its prodrug, heroin, do not have these same effects and so this is a distinct and rapid mechanism separating F/FA effects from the prolonged onset of respiratory depression caused by morphine-derived alkaloids. This distinction has significant consequences for the design and implementation of new pharmacologic strategies to effectively prevent F/FA-induced death.SIGNIFICANCE STATEMENT Deaths from fentanyl and fentanyl analogues (F/FA) are dramatically increasing in spite of the availability and awareness of naloxone as an opioid overdose reversal drug. This article reviews literature demonstrating that naloxone and other mu opioid receptor antagonists are ineffective against the underlying central noradrenergic effects of F/FA, which clinically manifest as the rapid onset of severe muscle rigidity and airway compromise (e.g. wooden chest syndrome) and are distinct from the respiratory depression seen with F/FA and morphine derived alkaloids. A physiologic model is proposed and implications for new drug development and treatment are discussed.},
issn = {0022-3565},
URL = {http://jpet.aspetjournals.org/content/early/2019/09/06/jpet.119.258566},
eprint = {http://jpet.aspetjournals.org/content/early/2019/09/06/jpet.119.258566.full.pdf},
journal = {Journal of Pharmacology and Experimental Therapeutics}
}